Prior art has used endocrine downregulation therapy to downregulate the growth of endocrine dependent cancers. Present invention takes exactly the opposite approach, using endocrine upregulation to accelerate the growth of cancer in conjunction with administration of phase specific chemotherapeutics to increase tumor kill rates and reduce systemic toxicity over prior art.
Additionally, prior art has been unable to achieve high cure rates using phase specific chemotherapeutics in non endocrine dependent metastatic cancers as well. Applicant has discovered that the primary reason is prior art""s failure to adjust the chemotherapeutic administration intervals for cancer""s accelerated growth rate over successive chemotherapeutic administrations. This failure results in the cancer""s return to an asynchronously cycling population which is mathematically a catastrophic event in the context of a phase specific administration regimen. Accordingly, applicant has disclosed methods for computing variable administration intervals that will keep the phase specific chemotherapeutic synchronized with the susceptible phase in the target cancer population. Alternatively, applicant has also disclosed methods of modulating the growth rate of endocrine dependent tumors by using endocrine hormones so as to keep a target cell population synchronized to a given administration regimen.
Definitions
As used in this application, the term xe2x80x9cendocrine dependent cancer(s)xe2x80x9d is used to mean cancers that have retained the functional hormone receptors normally present in the underlying tissue from which they arose and whereby cancer cells possessing these receptors will respond to administration of exogenous hormones by upregulating DNA synthesis. Examples of hormone receptors include, but are not limited to, estrogen receptors, progesterone receptors, and testosterone receptors.
Harrison""s Principles of Internal Medicine (14th ed. p. 527-536) categorizes prior art drug treatments used for cancer into four broad categories Chemotherapy, Endocrine Therapy, Immunotherapy, and Hematopoietic Growth Factors. Chemotherapy relates to substances toxic to cancer. Endocrine Therapy relates to inactivating or inhibiting steroids produced by the body that promote growth of certain cancers. Immunotherapy relates to enhancing various aspects of the natural human immune system to inhibit growth of cancer. Hematopoietic Growth Factors focus on enhancing recovery of bone marrow products for patients receiving myelosuppressive chemotherapy. Chemotherapy and Endocrine therapy have relevance to present invention and as such a brief background of prior art is provided.
Prior Art Chemotherapeutics (HPIM 14th ed. pgs. 527-534)
Most chemotherapeutic agents in use today are cell cycle active; that is, they are cytotoxic mainly to actively cycling cells. In addition, some cell cycle active agents are phase specific; that is, they are cytotoxic to cells in a particular phase of the cell cycle.
Alkylating agents are among the most widely used anti tumor agents and are efficient at cross-linking DNA, leading to strand breakage. Alkylating agents include cyclophosphamide, ifosfamide, melphalan, busulfan, mechlorethamine (nitrogen mustard), chlorambucil, thiotepa, carmustine, lomustine as well as platinum compounds such as cisplatin and carboplatin, which are not true alkylating agents also lead to covalent cross linking of DNA. These agents are best regarded as cell-cycle active but non-phase specific.
Purine/pyrimidine analogs/antimetabolites induce cytotoxicity by serving as false substrates in biochemical pathways. They are cell cycle active and specific mainly for the S phase. They include cytarabine, fluorouracil, gemcitabine, cladribine, fludarabine, pentostatin, hydroxyurea, and methotrexate.
Topoisomerase inhibitors interfere with the enzymes topoisomerase 1 and topoisomerase 2, responsible for mediating conformational and topological changes in the DNA required during transcription and replication. These agents include daunorubicin, doxorubicin, idarubicin, etoposide, teniposide, dactinomycin, and mitoxantrone.
Plant Alkaloids include vincristine, vinblastine, and vinorelbine which inhibit microtubule assembly by binding to tubulin and docetaxel and paclitaxel which function by stabilizing microtubules and preventing their disassembly. They are cell cycle active and cytotoxic predominately during the M phase of the cell cycle.
Antitumor Antibiotics include bleomycin that induces DNA strand breakage through free radical generation and Mitomycin C which cross links DNA. They are cytotoxic mainly during the G2 and M phase.
Other Agents include dacarbazine and procarbazine which act as alkylating agents to damage DNA and L-Asparaginase, the only enzyme used as a anti tumor agent, which acts by depletion of extracellular pools of asparagine.
Chemotherapeutic agents exhibit a dose response effect. At sufficiently low concentrations no cytotoxicity is observed. At increasing concentrations, cell kill is proportional to drug exposure. At high concentrations, the effect reaches a plateau. Drugs that are cell cycle active, but not phase specific, such as alkylating agents, characteristically have steep dose response curves: An increase in the drug concentration by an order of magnitude or more results in a proportional increase in tumor cell kill. By contrast, the dose response curve of phase specific agents, such as the antimetabolites, typically is linear over only a narrow range. These agents are less suitable for dose escalation and increased tumor cell kill is observed after prolonged exposure as a larger percentage of the tumor cells enter the cell cycle.
Chemotherapy employs two principles in administration: Therapeutic Index Dosaging and Cyclical Administration (HPIM 14th ed. 527-528 Pharmocodynamics section).
The therapeutic index represents the difference between the response of the tumor and response of normal tissue for a given dose of chemotherapeutic. Normal cells are also susceptible to the cytotoxic effects of chemotherapeutic drugs and exhibit a dose-response effect, but the response curve is shifted relative to that of malignant cells (see HPIM 14th ed. P. 528, FIGS. 86-3 enclosed). This difference represents the therapeutic index. The toxicity to normal tissue that limits further dose escalation is the xe2x80x9cdose-limiting toxicityxe2x80x9d. The dose just below this point is the xe2x80x9cmaximum tolerated dosexe2x80x9d. Proliferative normal tissues such as the bone marrow and gastrointestinal mucosa are generally the most susceptible to chemotherapy-induced toxicity. The usefulness of many chemotherapeutics is limited by the fact that they have a narrow therapeutic index (HPIM 14th ed. p.527).
Tumor regression in response to chemotherapy is logarithmic. A given dose of chemotherapy kills a constant percentage of cells. The xe2x80x9ccell kill ratexe2x80x9d (CKR) as used in this application is hereby defined as the percentage of cells that are killed during one cell division cycle at a given dosage of chemotherapeutic. The xe2x80x9ctumor kill ratexe2x80x9d as used in this application is hereby defined as the percentage of cells of a tumor that are killed during one administration cycle of a chemotherapeutic, which is directly proportional to the CKR and the number of cell division cycles that occur over the chemotherapeutic""s administration (or efficacy) period. As an example, if a 90% CKR chemo is administered over one cell division cycle, the tumor kill rate is also 90%. If the 90% CKR is administered over two cell division cycles the tumor kill rate is 99%. Conventional methods typically focus on xe2x80x9cmaximum tolerated dosesxe2x80x9d and extended administration periods.
Cyclical administration is required to allow normal rapidly proliferating cell populations to recover from the effects of chemotherapy. The number of administration cycles required to completely eradicate a tumor is dependent on the tumor kill rate of the therapeutic. To completely eradicate a tumor it is necessary to get below the mathematical 1 surviving cell number. As an example, to kill a 10 billion cell tumor with a chemotherapeutic that kills 95% of the tumor cells each administration cycle (5% survive) would require 8 cycles of chemotherapy (i.e. 10,000,000,000xc3x970.05xc3x970.05xc3x970.05xc3x970.05xc3x970.05xc3x970.05xc3x970.05xc3x970.05=0.39). In contrast, a chemotherapeutic with a 50% tumor kill rate would require 34 administration cycles to get the 10 billion cell tumor below the one surviving cell number (i.e. 10,000,000,000xc3x970.5 (34 times)=0.58). Likewise a 99% tumor kill rate would require only 6 administration cycles to get below the one surviving cell number.
Prior Art Endocrine Therapy (HPIM 14th ed. pgs. 534-535)
Endocrine therapy for hormone responsive malignancies depends on the presence of the appropriate hormone receptors, which in turn depends on the presence of those receptors (e.g. estrogen, progesterone, testosterone) in the underlying tissue from which the malignancy arose. Steroid hormones bind to specific intracellular receptors and induce a conformational change in the hormone-receptor complex that allows DNA transcription to proceed. Prior art hormonal antitumor agents are functional agonists or antagonists of the steroid hormones (HPIM 14th ed. p. 534).
The prior art use of endocrine therapy for malignancies possessing androgen, estrogen or progesterone receptors is presented in more detail by the specific cancers possessing these receptors.
Prostate Cancer: The androgen therapies for prostate cancer (HPIM 14th ed. p. 601) are all focused on reduction of androgen blood levels. The 4 methods under prior art are: 1) surgical castration and adrenalectomy to remove glands that produce androgens; 2) inhibition of pituitary gonadotropin and/or adrenocorticotropin production by estrogen therapy, hypophysectomy, or treatment with luteinizing hormone releasing hormone (LHRH) analogues such as Leuprolide or buserelin; 3) inhibition of androgen synthesis by the testes and adrenals (aminoglutethimide); and 4) inhibition of the binding of androgen to its receptor protein (cyproterone, flutamide, or bicalutamide).
Breast Cancer: Normal breast tissue contains both estrogen and progesterone receptors. Malignant breast tissue usually retain one or both of these phenotypes and methods for detecting the presence of these receptors is well established in prior art (HPIM 14th ed. p. 566). The Endocrine therapies for breast cancer are are grouped into 7 categories and summarized in Table 91-4 (HPIM 14th ed. p.566). They all focus on inhibiting endocrine dependent cancer cells from cycling by inhibiting or decreasing endogenous endocrine levels. 1) Castration removes the organs responsible for estrogen production, dropping endogenous estrogen levels and reducing the cancer""s rate of growth. 2) Antiestrogens (e.g. tamoxifen) compete with estrogens at the receptors and thus act as inhibitors. 3) Progestogens are anti-estrogenic. 4) Adrenalectomy is removal of the adrenal glands which decreases formation of estrogen precursors. 5) Aromatase inhibitors prevent aromatase from catalyzing reactions along several metabolic pathways involved in the synthesis of estrogens (BP p.94), thus reducing estrogen levels. 6) Hypophysectomy is surgical removal of the hypophysis or pituitary gland, thus reducing estrogen production by removing the upstream cascades that initiate its synthesis. And lastly, 7) additive androgen or estrogen therapyxe2x80x94androgens reduce estrogen by ablation of the ovaries (PDR p. 1407) and high estrogen concentrations stimulate 17xcex2-hydroxysteroid dehydrogenase which converts estradiol (the most potent estrogen) into a much less active form as well as reducing progesterone receptor formation (BP p. 92).
HPIM 14th ed. p. 565 also discloses use of adjuvant regimens which are summarized in Table 91-3. Four of the six methods use combinations of chemotherapeutics only. The other two use Tamoxifen, either by itself or after chemotherapy. Tamoxifen competes with estrogen at the receptors and thus acts as an inhibitor (BP p.94), once again consistent with the prior art approach of inhibiting the growth of the endocrine dependent cancer. A further prior art search was performed by reviewing the list of 44 articles posted by the University of Pennsylvania Cancer Center Website titled xe2x80x9cChemotherapy for Breast Cancerxe2x80x9d, a copy of which is included under the IDS. The prior art articles were consistent with HPIM""s disclosures. None of the studies proposed the use of endocrine cancer accelerants in conjunction with chemotherapeutics as proposed by present invention.
Additionally, prior art""s fairly high dose chemotherapy alone causes endocrine downregulation through ablation of organs responsible for endocrine production. In a study of 49 women undergoing chemotherapy for early stage breast cancer, 71% were subsequently diagnosed with ovarian failure (Science News, vol. 160 p. 89). Ovaries produce estrogen. The early and rapid bone loss in these women further corroborated this under-appreciated side effect of chemotherapy, which also results in endocrine downregulation. The adverse effect of endocrine downregulation and subsequent unresponsiveness of tumors to chemotherapeutics because of the resulting xe2x80x9cS-Phase Haltxe2x80x9d will be discussed in more detail below. Use of cancer accelerants proposed by present invention will allow for much lower doses of chemotherapeutic which will also provide the novel benefit of preventing the inadvertent xe2x80x9cchemotherapeutic castrationxe2x80x9d caused by prior art administration regimens.
In summary, all prior art endocrine therapies are used to inhibit cancer cells from cycling. The statement xe2x80x9c . . . combinations of chemotherapy with endocrine therapy are not usefulxe2x80x9d (HPIM 14th ed. p. 566, Endocrine Therapy section) are correct in light of prior art. However, this statement will no longer be true under present invention. It will be shown that combinations endocrine hormones with chemotherapy can be extremely useful and yield novel benefits over prior art such as increased tumor kill rates, reduced systemic toxicity, and the ability to maintain chemotherapeutic-to-cancer phase synchronization.
Unobviousness Over Prior Art
The compositions and methods of present invention are not obvious over prior art because they are exactly opposite to prior art. Prior art teaches use of endocrine therapies to inhibit cancer growth. Present invention teaches use of endocrine therapy to accelerate cancer growth. Prior art endocrine therapy is not used concurrent with chemotherapy whereas current invention uses endocrine administration concurrent with administration of chemotherapeutic(s) and is integrally dependent on its interaction with said chemotherapeutics unlike prior art endocrine therapy.
Novelty and Utility Over Prior Art
xe2x80x9cCancer Accelerantxe2x80x9d compositions and methods of present invention will yield a broad spectrum of new benefits over prior art including increased kill rate at a given dose of chemotherapeutic, or reduced dose of chemotherapeutic needed to achieve a given kill rate. Applicant will also show how to use endocrine accelerants to create user defined curative administration regimens, retain S-phase proportionality during chemotherapeutically induced accelerated growth, and how to create the 100% S-Phase tumor.
Additionally, applicant will disclose why prior art phase specific chemotherapeutic regimens are not curative but only moderately palliative. Corrected administration methods will be disclosed for maintaining phase specific chemotherapeutic-to-cancer phase synchronization in non endocrine dependent cancers. Applicant will also apply these corrected methods to endocrine dependent cancers, using endocrine accelerants to retain S-Phase proportionality and maintaining proper chemotherapeutic-to-cancer phase synchronization throughout the administration regimen. The novel compositions and methods disclosed will provide great utility over prior as they will yield curative versus palliative regimens.
The statement xe2x80x9c . . . combinations of chemotherapy with endocrine therapy are not usefulxe2x80x9d will no longer be true under present invention.
Utility of Present Inventionxe2x80x94Novel Mechanism of Action over Prior Art
The mechanism of action (MOA) of present invention has no comparable in prior art and can be summarized as follows: Current invention proposes releasing the brakes on the endocrine dependent cancer""s S phase halt, or greatly upregulating DNA transcription, at just the right time to result in a several-fold increase in the amount of damage inflicted by chemotherapeutic(s) to cancer cells during said accelerated DNA replication period or subsequently during DNA separation (S phase and M Phases respectively). Applicant also uses this stop/start (i.e. slow/fast) potential to maintain chemotherapeutic-to-cancer phase synchronization.
S Phase Halt: Endocrine dependent cancers are different from other cancers in one significant respect. In endocrine dependent cells, mutations indigenous to a malignant cell drive the cell through G1 just like in any other cancer. The difference, however, comes in the S phase, since endocrine hormones are not indigenously produced by the malignant cell. DNA transcription requires the endocrine hormones produced by some other organ to dock with and activate appropriate nuclear endocrine receptors which in turn activate or upregulate DNA transcription. The relevant schematized pathway for estrogen, progesterone, and androgens for upregulating DNA transcription in the S-Phase is shown in Biochemical Pathways p. 227 FIGS. 17.6-2 enclosed (i.e. via Group A nuclear receptors). In the absence of hormone, an inhibitory protein (Hsp 90, possibly also Hsp 70 and Hsp 56) binds to the receptor and covers the DNA binding/dimerization domain. Hormone binding causes a conformational change in the receptor that results in the dissociation of the inhibitory protein, formation of homodimers, entry of the homodimers into the nucleus and binding to the palindromic DNA response element, interacting with TFIIB and accelerating formation of the pre-initiation complex of transcription.
When endocrine levels are low or absent, the S phase can become disproportionately long as DNA transcription is stalled or greatly slowed down (i.e. what applicant refers to as the xe2x80x9cS Phase Haltxe2x80x9d). In this situation, a tumor would appear to have a disproportionate amount of cells in the S Phase, which can readily be determined under prior art flow cytometry and indirect S-Phase assessments using antigens associated with the cell cycle such as PCNA and Ki67 (HPIM 14th ed. p. 564).
Preface to Examplesxe2x80x94Cell Cycle Times and Cancer
The cell cycle time of normal rapidly proliferating cells (e.g. bone marrow, gastrointestinal stem cells, hair, and skin) is between 19 to 25 hours, in which time the cell spends xcx9c45% of its time in the G1 Phase, xcx9c32% in the S Phase, 18% in the G2 Phase and 5% of its time in the M Phase. Epithelial cells that line the lumen of the gut have an even shorter cell cycle time of xcx9c11 hours (MBOC 896).
A tumor""s cell cycle time is much longer by contrast. A typical tumor follows a Gompertzian growth curve (HPIM 15th ed . . . p. 530 FIGS. 84-1). In the fairly fast, non endocrine dependent tumor portrayed in the example, the growth from the first clinically detectable mass of 1 billion cells (xcx9c1 cubic cm) at day 100 to lethal burden of 1 trillion cells (xcx9c1 kg) at day 200 requires 10 cell cycles (i.e. 1 bil., 2, 4, 8, 16, 32, 64. 128, 256, 512, 1 tril) over a 100 day period which mathematically works out to a cell cycle time of 10 days (i.e. 100 days/10 cell cycles=10 days/cell cycle). The fastest growth rate occurs in the 50 days prior to the tumor reaching a clinically detectable mass and averages 2 days per cell cycle.
Non endocrine tumors such as colon cancer have a significantly longer cell cycle time than implied in the above representation. The colon cancer median survival of 6.5 months with only best supportive care (BSC) (PDR p. 2414) implies an xcx9c19 day colon cancer cell cycle time (i.e. 6.5 mo.=195 days and xcx9c10 cell cycles required from the first clinically detectable tumor of xcx9c1 bil. cells to lethal burden at xcx9c1 tril. cells=xcx9c19 days per cell cycle).
An endocrine dependent tumor can have an even longer cell cycle time. Although surgical removal of a tumor from the breast area and adjuvant chemotherapy is used as a first line of treatment for breast cancer, nearly half of patients treated for the apparently localized breast cancer develop metastatic disease. The median survival for metastatic disease to death for breast cancer is xcx9c2 years (HPIM 14th ed . . . p. 566). Starting with a metastasis that was at a clinically undetectable mass of xcx9c1 million cells (xcx9c1 xcexcL) when the primary breast tumor was detected, lethal burden of the metastasis would be reached in xcx9c20+ cell cycles over xcx9c2 years implying a cell cycle time in the ballpark of xcx9c30 days for the endocrine dependent metastatic cells. The similarity in duration of an endocrine dependent breast cancer""s cell cycle time to the menstrual cycle is not likely to be a mere coincidence. Normal breast tissue contains both progesterone and estrogen receptors. FIGS. 337-5 from HPIM 14th ed. p. 2101 shows the natural progesterone and estradiol levels over a menstrual cycle. A double peak of both estradiol and progesterone occurs only once a month around 24 days after start of menses. This likely acts as a natural, once a month, xe2x80x9cbrake releasexe2x80x9d on the S-Phase Halt which would also effect malignant breast cells that retained the progesterone and estrogen receptors.
Prior art endocrine downregulation/endocrine blocking therapies can extend the median survival to xcx9c4 years ( 3-5 or more per HPIM 14th ed . . . p. 566). Doubling the median survival time means doubling the cell cycle time from roughly 30 day to 60 days. Since, endocrines function in the S-Phase, the additional 30 day cell cycle extension would manifest itself as an unusually large proportion of cells stuck in the S-Phase.
The difference between the 19 day non-endocrine dependent colon tumor, the 30 day endocrine dependent breast tumor and the 60 day endocrine blocked tumor is outlined in TABLE 1 below as it will be used for illustrative purposes in some examples, particularly in determining frequency of administration. TABLE 1 starts with the colon tumor cell cycle of 19 days and displays the number of days it takes a cell to get through that phase as well as the corresponding % of cells one would expect to be in a given phase at any given time, based on the normal cell cycle phase distribution and before any chemotherapeutic administration regimen. The endocrine dependent tumors use the colon cancer model as a baseline and add any additional cell cycle time into the S-Phase as this is the phase where the lack of endocrines has an effect, both naturally in the 30 day breast cancer and artificially in the 60 day endocrine blocked tumor.
Chemotherapy is a balancing act between toxicity to the tumor and toxicity to normal rapidly proliferating cells in the body. The slower rate of tumor cell cycling (10 days to 30 days) versus xcx9c1 day for normal rapidly proliferating cells has been a major impediment to effective treatment of tumors under prior art. Present invention will show how to get around this issue.
Reduction to Practicexe2x80x94Redefining Administration Intervals
Due in part to the novel methods of present invention which use phase specific chemotherapeutics and in part to the inability of prior art to define or implement proper methods of using phase specific chemotherapeutics, it is also necessary to define novel methods for computing appropriate administration intervals for use with phase specific chemotherapeutics. This method will yield curative results versus prior art""s palliative results.
Prior art tends to favor high dose regimens administered several weeks apart. There is no rational basis for doing this and mathematically it can never provide a curative result. To the contrary, present invention favors the lowest dose that will induce a desired kill rate in the phase (i.e. 95-100%) and has the shortest in vivo efficacy time (i.e. shortest terminal half life) and administration that is rationally synchronized with respect to the cancer cell cycle. The optimal phase specific chemotherapeutic under present invention should induce a kill rate in the phase of xcx9c95-100% and have an in vivo efficacy period (terminal half life) of 3 or 4 hours to minimize systemic cytotoxicity.
The major flaw in prior art is that it erroneously uses a fixed administration interval (AI), usually based on some calendar schedule. A variable AI is required to adjust for the accelerated tumor growth and proportionately reduced cell cycle and phase times as the tumor moves backward along the Gompertzian growth curve (HPIM 15th ed . . . p. 530 FIGS. 84-1) over the course of a chemotherapeutic regimen. Without this adjustment the AI will very quickly be much greater than both the cancer cell cycle time, susceptible Phase time, and most importantly administration of the chemotherapeutic will no longer be appropriately synchronized to the cancer cell population.
The Gompertzian growth curve shows a fairly abrupt growth rate change on either side of the 1 billion cell level. Below that level a tumor grows up to 5 times faster than above it. Cancer is the accumulation of about half dozen or so genetic xe2x80x9caccidentsxe2x80x9d or lesions in proto-oncogenes and/or tumor suppressor genes. So far about 60 proto-oncogenes (MBOC 1279) have been discovered and presumably there are roughly as many tumor suppressor genes. Examples of proto-oncogene products include practically every type of molecule involved in growth from protein growth factors, growth factor receptors, growth signal transduction molecules, to gene regulatory proteins. Growth is a balancing act where normally inhibitory influences predominate. Cancer""s oncogenes and/or defective tumor suppressor genes tip the balance to where growth predominates. As tumor cells grow they become crowded and starved of oxygen an nutrients, causing them to upregulate production of angiogenic growth factors ( a process normal to all cells under such conditions) and neovascularize the tumor. Endothelial cells (i.e. blood vessel cells) however are not mutated and are still subject to growth controls (such as density dependent inhibition of cell division vial P27 Kip 1 upregulation) which means they will eventually slow or stop angiogenesis, especially in particularly crowded areas, even in light of the high levels of angiogenic factors issued by the crowded tumor cells. As tumor cells crowd each other beyond a certain point they can no longer get enough nutrients to sustain their overexpression of growth related proteins, angiogenic growth factors, or the 2,000 to 5,000 other structural and regulatory proteins required for cell growth and division.
Of critical relevance to present invention is understanding what happens when a chemotherapeutic hits a tumor like the one described above. Wiping out a large part of the crowded tumor is a windfall for the surviving cells. They now find themselves in a well neovascularized, oxygen and nutrient rich, empty space. Add to that a genetic mutation profile that is permanently switched on for growth and they will immediately resume fulfilling their genetic destiny. This will manifest itself as them resuming their earlier accelerated growth (or possibly even faster) until they have once again crowded themselves to the point of a lower growth rate.
In our colon cancer example, that would imply the 19 day cancer cell cycle time above the 1 Bil. cell level becomes a 3.8 day cell cycle time after a chemotherapeutic reduces the tumor""s size below the 1 bil. cell level. Using a typical S-Phase chemotherapeutic which kills 100% of cells in the S-Phase, for a total tumor kill rate of 32%, the surviving cancer cells will be able to run through nearly 2 cell cycles (i.e. quadruple) before the next dose on chemotherapeutic is administered on day 7. In reality, this will never happen because well before they complete even 1 cycle the cell mass will once again reach the 1 billion mark and downregulate itself to the 19 day cell cycle.
When an AI becomes longer than the susceptible phase of the cycle, cells slip through the phase into non susceptible phases. When the AI becomes longer than the cell cycle itself, one or more cell cycles of the cancer can occur before the next chemotherapeutic administration. Regrowth, or even accelerated growth, results in the cancer cell population being phase asynchronous again, which is a catastrophic event for a phase specific administration regimen. AI""s of a phase specific chemotherapeutic must precisely follow the phase progression of the cancer cells through the cycle, with each successive administration of chemotherapy occurring shortly before each successive batch of cells that entered the susceptible phase during the administration interval have had time to exit into a non susceptible phase. The return to an asynchronously cycling population will mathematically yield a result over time that is basically indistinguishable from using a non phase specific chemotherapeutic with a kill rate equal to the phase kill rate of the chemotherapeutic times the percent of cell in that phasexe2x80x94which at a best case 100% S-Phase kill rate times the 32% of cells in S-Phase is comparable to a non phase specific chemotherapeutic with a paltry 32% kill rate.
As an example, the studies of Camptosar(copyright) follow the prior art administration methods of using a fixed AI. TABLE 2 below was constructed from Study 3 (PDR p. 2413 Table 2) and shows the mathematically predicted progression of the tumor from the first clinically detectable mass to lethal burden for best supportive care as well as under the two different administration regimens used in Study 3. The 125 mg dose was administered once every 7 days for 4 weeks, followed by 2 weeks off for 4 months (3 cycles). The 100 mg dose was administered in the same manner but for only 3 months (2 cycles). In TABLE 2 below, the tumor""s typical exponential growth rate has been computed using the equation: (starting # of cells)xc3x972(xcex94t/19); where xcex94t the relevant time period in days and 19 days is the colon cancers self limiting growth rate cell cycle. Tumor regression was computed using 32% of cells being killed each administration as if with a non phase specific chemotherapeutic. The mathematical model projects a lethal burden for the 125 mg regimen somewhere between 315-322 days compared to the 321 days (10.7 mo.xc3x9730 days) median survival observed, and projects lethal burden for the 100 mg dose at between 273-280 days compared to 279 days (93 mo.xc3x9730 days) median survival observed. The math supports that this S-Phase chemotherapeutic has a close to 100% S-Phase kill rate at both doses, however in the absence of the proper AI results in only modest palliative rather than curative affect.
Present invention proposes a method of administering phase specific chemotherapeutics using an administration interval defined by the equation:
AI=(DCCC)xc3x97(% CIP)xc3x97(CF)
Where:
AI=Administration Interval (in days)
DCCC=Duration of the Cancer Cell Cycle (in days)
% CIP=the percentage of cancer Cells in the Phase in which the chemotherapeutic exhibits toxicity (e.g. determined by flow cytometry for S-Phase)
CF=Confidence Factor, which is a number between 0 and 1, preferably between 0.6-0.8 that reduces the AI to account for margin of averaging error
Note: Any suitable time increment may be used, e.g. days may be substituted with hours as long as the same time increment is used for all variables
Note: The equation may be also written as AI=(Duration of Relevant Phase in days)(CF)